anti ht beyond low bp ht beyond low bp.pdf · 130/80 220/130 190/110 ccb ace-i arb ... 4588 4490...

1

1

JIKEI Satellite Meeting

New Evidence in Management of High Risk Hypertension

in Asian Population : Roles of ARB

Can We Prevent Stroke for High Risk

Hypertension Patients Beyond BP Reduction

Associate Professor Somsak Tiamkao

Division of Neurology, Department of Medicine

Faculty of Medicine, Khon Kaen University

E-mail : [email protected]

25 November 20072

��

��

�

3

Relationship between BP and occurrence of first stroke and effect of BP lowering treatment in preventing stroke well established

¾ of patient with acute stroke have high BP at presentation, 50% have history of HT

BP declines spontaneously over first week in 2/3 of patients

Fact

4

There is no general agreement on

BP management in acute phase

Current opinions, SBP > 220 mmHg,

DBP > 120 mmHg should treated

Recommended cut off values for treat are

lower in patients treated with rt PA

Fact

5

Purpose

Role of BP in stroke

Management of BP in acute

ischemic stroke patients

JIKEI Heart study: Personal views

6

Conflict of interest

No any research funding, joined

meeting or conference, and clinical trials

Never used ARB for ischemic stroke

patients

2

7

Q U E S T I O N S ?Question?

Question?

Question?

Question?

Question?

Question?

Question?

Question?

Question?

130/80 220/130 190/110

CCB ACE-I ARB

Rx No Rx No answer

8

Real life practice

Women 51 yr, DM, HT, CKD

On enalapril and diovan

Sudden onset of left hemiparesis

CT-brain: lacunar infarction

BP 130/80 mmHg

Left hemiparesis, fully of consciousness

9

Real life practiceFemale 65 yr old

Underlying HT(Rx with ccb),dyslipidemia,DM

Sudden developed right hemiplegia

and global aphasia

BP 200/100 mmHg

CT brain showed normal study

( 4 hr after onset)

10

How to manage these problems?

What is a diagnosis?

Treat or Not treat BP ?

How to treat ?

What is an anti HT drug ?

11

Topics

1. Effect of BP in stroke patients

2. Role of antihypertensive drug in primary and

secondary prevention

3. Management of BP in acute ischemic stroke

4. Personal views on JIKEI Heart study

http://www.cdc.gov/nchs/about/otheract/hp2000/hdspr/hdsprog.htm

3

13

Stroke in ThailandStroke in Thailand

� Bangkok metropolis (1983) = 690 : 100,000 age over 20

(Viriyavejakul A, et al. 6th Excerpta Medical No.22; 1983: 10)

� Stroke in the elderly (1998); overall 1.12%

Central 1.99 North 0.6

South 1.5 Northeast 0.6

(Viriyavejakul A, et al. J Med Assoc Thai 1998; 81: 497-505)

�Thai Epidemiology Stroke Study (TES Study 2004): Stroke in age 45-80 years = 2.46%

Prevalence

CINP Asia pacific Regional Meetng March 14-17, 2006, Pattaya, Thailand Abstracts P54-55

14

15

:;<=>?@AB:;<=>?@AB:<CDEF:<CDEF Stroke Stroke

�� 16

Stroke Mortality Rate by Age1

Blood Pressure and Stroke Mortality

Stroke mort al ity rate in each decade o f age vs. usual b lood pressure at the star t of the decade.

A meta-analysis involving 1 mill ion parti cipants in 61 cohort studies to determine the relevance of

blood pressure to risk of disease in patients of di fferent ages.1. Prospective Studies Collaboration. Lancet 2002; 360:1903-1913.

6

Primary prevention

P<0.00001525:835All trials

157:27213 others

37% (SD4) reduction 101:134MR C65-74 trial

105:162SHEP

60:109MR C35-64 trial

102:158HDFP trial

Treatment worseTreatment better

(95% confidence intervals)

Odds ration N of strokes Trial

A net reduction of 5-6 mmHg DBP and 10-12 mmHg with a

38% reduction in the risk of fatal and non-fatal stroke18

PERINDOPRIL PROTECTION AGAINST RECURRENT STROKE STUDY

The firs t randomized trial of ACE

inhibitor-bas e d tre atment in patients

with a his tory of c ere brovas cular

dis e as e

Nea l B, Ma cMa hon S. J Hype rtens . 19 95 ;13:18 69 -1 87 3.

Secondary prevention

4

19 20

Stroke: Survival Curve

0 500 1000 15000

0.010.02

0.030.04

0.05

0.06

Ka

pla

n-M

eie

r R

ate

s

Ramipril

Placebo

Days of Follow-upRR= 0.68

(0.56-0.84)

P= 0.0002

�� 08/2002BMJ

RRR 32%

21

Reduction in the Risk of Stroke1

No significant difference in CV death and MI vs. ateno lol. Risk reduction = relative risk vs. atenolol.

Losartan (n) 4605 4528 4469 4408 4332 4273 4224 4166 4117 3974 1928 925

Atenolol (n) 4588 4490 4424 4372 4317 4245 4180 4119 4055 3894 1901 897

Number at risk

161. Dahl?f B et al. Lancet 2002;359: 995-1003.

Atenolo

l

Pro

por

tio

n o

f p

atie

nts

wit

h f

irst

eve

nt(%

)

6

7

0

2

3

4

5

0 6 423012 18 24 36 48 54 60 66

Time (months)

Losartan

1Adjusted risk reduction 24.9%, p = 0.0010Unadjusted risk reduction 25.8%, p = 0.0006

Fatal and nonfatal stroke

8

22

Relationship between BP and occurrence of first stroke and effect of BP lowering treatment in preventing stroke well established

¾ of patient with acute stroke have high BP at presentation, 50% have history of HT

BP declines spontaneously over first week in 2/3 of patients

Fact : Acute stroke

23

Cerebral Blood Flow:CBF

CBF of 50-70 mL/100g/min- normal

CBF of 20-50 mL/100g/min- reduced flow

CBF of 15-20 mL/100g/min- neuronal quiescence

CBF <15mL/100g/min- neuronal death

24

Equations

MAP = 2/3 DBP + 1/3 SBP

MAP = DBP+ 1/3(SBP-DBP)

CPP = MAP S ICP

CBF = CPP/CVR

Mean arterial pressure (MAP) diastolic blood pressure (DBP) systolic blood pressure (SBP)

Cerebral perfusion pressure (CPP) intracranial pressure (ICP) cerebrovascular resistance (CVR)

5

25

CBF: CPP/CVR

Systemic hypertension in acute ischemic stroke

is common

Physiologic response for maintain adequate

cerebral perfusion to ischemic penumbra

Stroke Council of American Stroke Association

UAgainst treating HT in acute strokeV

26Mochizuki et al. Lancet 2007;369:1431-9

Relationship between cerebral perfusion

pressure and cerebral blood flow.

27

Do treat HT in acute cerebral infarction

Decreased recurrent stroke, ICH

Hypertensive encephalopathy may be

associated with stroke

Severe HT may cause acute cardiac strain

HT may cause vasogenic brain edema

28

rt-PA era after June 1996

Parenchymal bleeding, hemorrhagic

transformation increasing in high BP

Main motivation for BP management in

acute phase

Do treat HT in acute cerebral infarction

29

Do not treat HT in acute cerebral infarction

Brain autoregulation for control CBF

Impaired autoregulation in stroke

Increased watershed infarction

Increased turbulent flow of VV.

30

6

31

BP in the ED and on Admission to the Inpatient

Clinic According to OCSP Classification

Mean ±±±± SD BP, mm Hg

87 ±±±± 21153 ±±±± 4284 ±±±± 18 148 ±±±± 46POCI (n = 12)

96 ±±±± 14181 ±±±± 31‡‡‡‡90 ±±±± 11††††170 ±±±± 30LACI (n = 34)

90 ±±±± 13169 ±±±± 2885 ±±±± 14165 ±±±± 26PACI (n = 30)

88 ±±±± 17165 ±±±± 2779 ±±±± 13160 ±±±± 22TACI (n = 16)

Diastolic

(AD)

Systolic

(AD)

Diastolic

(ED)

Systolic

(ED)

OCSP

Classification

32

Severity of Stroke on Admission to the Inpatient Clinic

According to OCSP Classification

4 ±±±± 131 ±±±± 3513 ±±±± 210 ±±±± 5PACI (n = 30)

Mean ±±±± SD Score

5 ±±±±04 ±±±± 88 ±±±± 327 ±±±± 11POCI (n = 14)

3 ±±±±153 ±±±± 3614 ±±±± 27 ±±±± 7LACI (n = 34)

5 ±±±± 08 ±±±± 711 ±±±± 219 ±±±± 9TACI (n = 16)

Rankin

Modified Scale

Barthel

Index

GCSNIH ScaleOCSP

Classification

33

BP in the ED and on Admission to the Inpatient

Clinic According to TOAST Classification

Mean ±±±± SD BP, mm Hg

86 ±±±± 18167 ±±±± 3481 ±±±± 15163 ±±±± 33LVA (n = 29)

96 ±±±± 14‡181 ±±±± 34‡90 ±±±± 11†170 ±±±± 30LACI (n = 34)

91 ±±±± 14162 ±±±± 2884 ±±±± 14157 ±±±± 29Cardioe (n = 28)

Diastolic

(AD)

Systolic

(AD)

Diastolic

(ED)

Systolic

(ED)

TOAST

Classification

34

Severity of Stroke on Admission to the Inpatient Clinic

According to TOAST Classification

3 ±±±± 1‡53 ±±±± 36 ‡14 ±±±± 2‡7 ±±±± 7†LACI (n = 34)

Mean ±±±± SD Score

4 ±±±± 122 ±±±± 3412 ±±±± 415 ±±±± 11LVA (n = 29)

4 ±±±± 113 ±±±± 2111 ±±±± 317 ±±±± 9Cardioe (n = 28)

Rankin Modified

Scale

Barthel

Index

GCSNIH ScaleTOAST Classification

35

�Mild Impairment

��Moderate Impairment

�Severe Impairment/Death

ED AD 24 Hours 4 Days Final

Systolic

Diastolic

36

�Therapy Started or Increased

��Therapy Tapered or Stopped

�Therapy Unchanged

•••• No Therapy

Systolic

Diastolic

ED AD 24 Hours 4 Days Final

7

37

ConclusionHighest BP at ED and 24 hr was seen in LACI

LACI had less severe neurological deficit

LVA and CE had a lower BP and more severe

38

39

Mortality rate at 1 month Mortality rate at 12 months �

�

��

� � �

�

<101 101-120 121-140 141-160 161-180 181-200 201-220 >220

Systolic BP on admission (mmHg)

80

70

60

50

40

30

20

10

0

Mortality rate (%

)

40

Diastolic BP on admission (mmHg)

>61 61-70 71-80 81-90 91-100 101-110 111-120 >120

100

90

80

70

60

50

40

30

20

10

0

Mortality rate (%

)

�

��

��

�

�

41

Relationship between early or late stroke mortality

and admission systolic blood pressure (SBP) values

0.0041.072 (1.022-1.123)>130

0.0161.175 (1.031-1.340)≤ 1301-year

mortality

0.0011.102 (1.042-1.166)>130

0.0031.282 (1.086-1.513)≤ 1301-month

mortality

P-value Hazard ratios (95% CI)SBP

(mmHg)

Outcome

42

0.001107 (37.8)14 (16.3)Neurological damage

0.04359 (20.8)27 (31.4)Cardiovascular disease

0.86575 (26.5)22 (25.6)Infections

0.01142 (14.9)23 (26.7)Other or unknown

12 month

P-value SBP > 130 (n = 883)

SBP ≤130

(n = 247)Causes of death

0.24618 (09.1)7 (14.9)Other or unknown

0.96852 (28.0)13 (27.7)Infections

0.00423 (12.4)14 (29.7)Cardiovascular disease

0.00597 (50.5)13 (27.7)Neurological damage

1 month

8

43

Conclusion

Every 10 mmHg rise in admission SBP above

130 mmHg, early and late mortality increase by

10.2, 7.2%

Every 10 mmHg below SBP 130 mmHg, early

and late mortality increase 28.2, 17.5%

SBP 141-160 mmHg is optimal BP

44

45 46

47

Relationship between first BP variables and outcome:

Rankin >3 vs ≤≤≤≤3

NS0.70-6.332.11≥≥≥≥110 (n = 46) vs 91-109

NS0.49-2.361.07≤≤≤≤90 (n = 265) vs 91-109 (n = 92)

First DBP

NS0.58-3.311.38≥≥≥≥150 (n = 323) vs 131-149

NS0.43-2.831.10≤≤≤≤130 (n = 97) vs 131-149 (n = 74)

First SBP

P-value 95% CIORFirst BP-values (mm Hg)

48

9

49

The mean profiles of SBP with 95% CI according to favorable

outcome (mRS 0 to 1) and unfavorable outcome (mRS 2 to 6)

Favorable outcome

Unfavorable outcome Mean Systolic Blood Pressure (mmHg)

Hours after Admission

50

The mean profiles of SBP with 95% CI according to favorable

outcome (mRS 0 to 1) and unfavorable outcome (mRS 2 to 6)

Favorable outcome Unfavorable outcome

Mean Systolic Blood Pressure (mmHg)

Hours after Admission

51 52

Mean value and 95% Cl of infarct volume on

days 4 to 7 by SBP levels on admission

Mean value and 95% Clof infarct volum

e (cc)

53

Mean value and 95% Cl of infarct volume on

days 4 to 7 by DBP levels on admission

Mean value and 95% Clof infarct volum

e

(cc)

54

U shaped effect

Every 10 mmHg ≤≤≤≤180 mmHg SBP, ≤≤≤≤100 mm DBP

○neurological deterioration 6%

○poor outcome 25%

○mortality 7%

○mean infarct increased 7.3 cm3

Results

10

55

U shaped effect

Every 10 mmHg > 180 mm SBP, > 100 DBP

○neurological deterioration 40%

○poor outcome 23%

○no effect on mortality

○mean infarct increased 5.5 cm3

Results

56

57

Previous data demonstrate the detriment

effect of both low and high MAP in patient

presenting with ischemic stroke

Based on single BP at ER, mortality at 30-day

Effect of change in SBP and DBP in 180 min

Fact

58

Changes in Blood Pressure Between Admission

and the First Day : Stroke Outcome

<0.001110 ±±±±70

(52)

80 ±±±±64

(195)

137 ±±±±60

(49)

<0.001108 ±±±±73

(66)

77 ±±±±60 (147)133 ±±±±66 (56)Volume of infarct,

mean±±±±SD, mL

0.00920.0 (45)9.0 (167)25.0 (44)0.06613.0 (54)10.6 (151)23.5 (51)Mortality at 3 months, %

0.01462.2 (45)53.3 (167)77.3 (44)<0.00157.4 (54)49.0 (151)90.2 (51)Poor neurological

outcome, %

<0.00135.8 (53)14.2 (197)56.1 (50)<0.00130.3 (66)13.6 (177)54.4 (57)Early neurological

deterioration, %

P

Value

Increase

>0 mmHg

Drop

0-20 mmHg

Drop

>20 mm Hg

P

Value

Increase

>0 mm Hg

Drop

0-20 mm Hg

Drop

>20 mm Hg

Diastolic Blood Pressure Systolic Blood Pressure

59

Comparison of BP values derived from measurements obtained during the

first 180 minutes, patients with/ without 90-day mortality

30 (22, 50)47 (29, 70)Median (IQR)

37 (23.0)50.8 (28.8)Mean (SD)

0.047Differential

160 (143, 194)174.8 (146, 188)Median (IQR)

168.6 (35.9)171.1 (31.8)Mean (SD)

0.91Baseline

Systolic BP, mm Hg

Wilcoxon

p value

No,

n = 51

Yes,

n=2090-day mortality

60

Comparison of BP values derived from measurements obtained

during the firs 180 minutes, patients with without 90-day mortality

25 (16,37)44.5 (31, 58)Median (IQR)

27.3 (17.1)46 (20.7)Mean (SD)

<0.001Differential

80 (67.90)90.5 (67, 100)Median (IQR)

80.2 (18.6)86.4 (25.4)Mean (SD)

0.91Baseline

0.27Diastolic BP, mm Hg

Wilcoxon

p value

No,

n = 51

Yes,

n=2090-day mortality

11

61

CBF in penumbra depends on systemic BP and collaterals

until the occlude artery is recanalized

Lower variability of DBP during 24hr with favorable outcome

Reflect state of auto-regulation and BP control

Benefit to keep BP at a reasonable lower overall level and

less variable over time

Sudden drop of BP with short half-life drug should avoided

Conclusion

62

Extreme variations in difference SBP/DBP in acute

phrase are also predictive of a poor outcome

Human brain has decreased ability to autoregulation

Fluctuation in BP may lead to under-or overperfusion

of delicate ischemic neurons

Increased BP can lead edema and hemorrhage

Decreased BP can lead infarction size

Conclusion

63 64

Objective

○BP in acute stroke

○Relationship with outcome

Methods

○17398 stroke, confirm with CT-brain

○Acute stroke within 48 hr

65

SBP (mmHg)

<120 735 (4.2)

120-139 2476 (14.2)

140-159 4859 (27.9)

160-179 4541 (26.1)

180-199 2933 (16.9)

>200 1854 (10.7)

66

12

67 68

Patients with SBP < 150 mmHg, every 10 mmHg

fall in BP, increase risk of early death 17.9%,

death or dependency at 6 months 3.6%

Recurrent ischemic stroke within 14 days was

increasing 4.2% every 10 mmHg increase in SBP

Results U shaped

69

Low BP associated with early death from CAD

Low BP could promote reduced CBP, cardiac

perfusion, CAD

CAD causes hypotension, low CBP, large

infarction, poor outcome

High BP caused cerebral edema, recurrent stroke

70

Patient with low BP might benefit from

having it raised and cassation of prior

antihypertensive drug

Patient with high BP might have a better

outcome if they continue prior

antihypertensive drug or appropriate drug

Conclusion

71 72

Antihypertensive drug indicate an emerging conceptual shift from lowering BP to specific organ protective effects

Benefit beyond the effects of BP reduction

ACE inhibitor, ARB showed protective against heart and renal

ARB is protective against stroke

Fact

13

73

Prospective, double-blind, placebo-controlled, RCT

500 patients with cerebral infarction within 36 hr

BP ≥≥≥≥200 mmHg SBP and/or ≥≥≥≥110 mmHg DBP 6-24 hr

BP ≥≥≥≥180 mmHg SBP and /or ≥≥≥≥105 mmHg DBP 24-36 hr

Target reduction of BP was 10-15% within 24 hr

Patients

74

140/90180/105

200/110

75

Baseline Characteristics on Admission, Barthel Index at 3 Months,

Cumulative Mortality Until 12 Months, and Vascular Events

190 ±±±±19.7188±±±±20.9Systolic

99 ±±±±13.099±±±±14.9Diastolic

Blood pressure on study onset, mm Hg

102 ±±±±14.9103±±±±14.0Diastolic

199 ±±±±22.9196±±±±23.1Systolic

Blood pressure on admission, mm Hg

Placebo Candesartan Cilexetil

76

200

150

100

50

0

systolic

diastolic

77

Safety trial stopped premature, (342/500), because of an imbalance outcome

164/166 in placebo group was treated on day 7 (BP>140/90)

Mortality rate 2.9 vs 7.2%

Vascular event 9.8 vs 18.7%

Result

78

Baseline Characteristics on Admission, Barthel Index at 3 Months,

Cumulative Mortality Until 12 Months, and Vascular Events

11Pulmonary embolism

11Noncardiovascular mortality

1913Cerebrovascular events (fatal and nonfatal)

31 (18.7)*17 (9.8)*Vascular events*

102Cardiovascular events (fatal and nonfatal)

12 (7.2%)5 (2.9%)Cumulative 12-mo mortality

88.9 ±±±±19.987.0±±±±22.9Barthel Index 3 mo

64.1 ±±±±27.560.0±±±±30.2Barthel Index day 0

29.729.9Duration of symptoms until study onset, h

Placebo Candesartan Cilexetil

14

79

7-day course of candesartan after acute ischemic stroke significantly improves cardiovascular morbi and morta

However, favorable outcome is not achieved when started 7 days offer stroke

Candesartan showed profoundly effect on cardiovascular, lower incidence of myocardial infarction

Recurrent stroke did not difference

Neurohumoral inhibition has benefit effect in cerebral and myocardial infarction

Conclusion

80

81

Fig. Automated brachial blood pressure and heart rate profile for 16 h after first dose. Lisinopril, n= 17; Placebo, n = 18. Data

presented as mean±±±± standard error bars. *Statistically significant BP reduction in lisinopril group compared to placebo for

systolic (SBP), mean (MAP), and diastolic (DBP) blood pressure (p<.05) between hours 4 and 8

82

Fig. Automated brachial blood pressure and heart rate profiles for 16 h at baseline and day 14 of therapy.

Lisinopril, n=12; Placebo, n= 16. Data presented as mean ±±±± standard error bars. *Statistically significant BP

reduction in lisionopril group compared to placebo for systolic (SBP), mean (MAP) (P>.01), and diastolic (DBP)

blood pressure (P>.05)

83 84

175

170

165

160

155

150

145

140

135

130

Systolic Blood Pressure

mmHg

Placebo Low dose High dose

D0 D1 D2 D3 D4 D5 D0 D1 D2 D3 D4 D5

D0 D1 D2 D3 D4 D5

15

85

Diastolic Blood Pressure

100

95

90

85

80

75

70

65

mm Hg

Placebo low-dose high-dose

D0 D1 D2 D3 D4 D5

D0 D1 D2 D3 D4 D5

D0 D1 D2 D3 D4 D5

86

1.41(0.30,6.60)62/926/8Profound decrease >=20%

1.94(0.84,4.50)62/9230/37Moderate decrease 10 to <20%

0.97(0.40,2.32)62/9220/30Slight decrease <10%

2.12(0.71,6.36)62/9215/18Unchanged/increased

Low-dose DBP change subgroups vs Placebo

3.69 (1.80,7.58)62/9272/83High-dose vs Placebo

Peto odds rations

(95% C.I)

1.55(0.82,2.94)62/9271/93Low-dose vs. Placebo

Peto odds ratios

(95% C.I)

Placebo

n/N

Nimodipine

n/N

Death or dependency

87

Peto odds ratios

(95% C.I)

Peto odds rations

(95% C.I)

Placebo

n/N

Nimodipine

n/N

Death or dependency

4.36(1.63,11.7)62/9225/26Profound decrease >=20%

2.97(1.16,7.63)62/9225/28Moderate decrease 10 to <20%

2.60(0.82,8.27)62/9214/16Slight decrease <10%

1.79(0.44,7.24)62/928/10Unchanged/increased

High-dose DBP change subgroups vs. Placebo

88

89 90

16

91

Fact USA guideline; SBP > 220, MAP > 130 mmHg

154 ischemic stroke

66% previous HT

51% use anti HT

10.71% severe HT on arrival

Median BP 160/80 mmHg

MAP 106 mmHg

92

Fact (4 day hospitalization)

11% had hypotension (SBP < 120, MAP < 85 mmHg)

22% had one episode of severe HT

69% had one episode of hypotension

Adherence to stroke guideline ??

93

The JIKEI HEART Study

The First Large-scale Intervention Trial

of an ARB in a Japanese Population


Study Hypothesis

� Treatment with a valsartan-based therapy will

yield additional protective benefits, compared

with conventional treatment, beyond those

attributable to blood pressure (BP) control


Study Endpoints

Primary endpoint: Combined endpoint of CV morbidity and mortality

– Hospitalization for stroke or TIA (Transient Ischemic Attack)

– Myocardial infarction (MI)

– Hospitalisation for congestive heart failure (CHF)

– Hospitalisation for angina pectoris

– Dissecting aneurysm of the aorta

– Doubling of serum creatinine or transition to dialysis

Secondary Endpoints:

– Each component of the primary endpoint

– Death from any cause


Baseline Characteristics

72 (11)

24(3)

71 (11)

24(3)

Heart rate (beats/min)

BMI (kg/cm2)

81.4 (10.8)81.4 (10.5)

Diastolic BP [DBP]

(mmHg)

138.8 (10.6)139.2 (11.4)

Systolic BP [SBP]

(mmHg)

262 (17%)259 (17%)Current smoker

65 (10)65 (10)Age (years)

517 (34%)521 (34%)Female

1,023 (66%)1,020 (66%)Male

Non-ARB arm

(n=1,540)

Valsartan arm

(n=1,541)

Clinical

characteristics

Note: Data are mean (Standard Deviation) or Number (%)

17


Medical History at Baseline

314 (20%)315 (20%)Diabetes mellitus

813 (53%)812 (53%)Hyperlipidaemia

174 (11%)176 (11%)Heart failure

522 (34%)514 (33%)Coronary heart disease

1,341 (87%)1,358 (88%)Hypertension

Non-ARB arm

(n=1,540)

Valsartan arm

(n=1,541)Concomitant Diseases


Medications at Baseline

37 (2%)42 (3%)Fibrate

490 (32%)461 (30%)Statin

126 (8%)117 (8%)Other diuretics

64 (4%)52 (3%)Anti-aldosterone agent

39 (3%)29 (2%)Thiazide

93 (6%)74 (5%)αααα-blocker

502 (33%)486 (32%)ββββ-blocker

525 (34%)548 (36%)ACE Inhibitor

1,011 (66%)1,041 (68%)CCB

Non-ARB arm (n=1,540)

Valsartan arm (n=1,541)

ACEI: angiotensin converting-enzyme inhibitor; CCB: calcium channel blocker


The JIKEI HEART Study was Halted Early Due to Unequivocal Benefit from Valsartan

� On a recommendation from the Data and Safety Monitoring Board

(DSMB), the JIKEI HEART Study was halted early for ethical

reasons, after 3.1 years because valsartan treatment was

associated with a reduction in the primary endpoint (combined

endpoint of cardiovascular morbidity and mortality)

� Originally, this study was planned to be conducted for 3.5 years

100


Blood Pressure (BP) Results

101


Primary Endpoint Result


Primary Endpoint

0 6 12 18 24 30 36 42 48

Number at risk

Valsartan 1,541 1,504 1,441 1,257 1,092 855 689 368 368

Non-ARB 1,540 1,502 1,447 1,262 1,075 835 657 344 343

15

10

5

0

Even

t ra

te (

%)

Valsartan arm (92 events)

Non-ARB arm (149 events)

HR=0.61, p=0.0002

95% CI 0.47–0.79

39%

18


Effect of Treatment on Endpoints

Primary endpointComposite endpoint

Secondary endpointsStroke/TIA

Myocardial infarction

Hospitalisation for angina pectoris

Hospitalisation for Heart Failure

Dissecting aortic aneurysm

Transition to dialysis, doubling

of serum creatinine levels

All cause mortality

Cardiovascular mortality

0.0002

0.0280

0.7545

0.0001

0.0293

0.0340

0.8966

0.7537

0.9545

P-value

TIA = transient ischaemic attack

Incidence increasedIncidence of endpoint reduced

0.125 0.25 0.5 1 2 4


New or Recurrent Stroke

0 6 12 18 24 30 36 42 48

Number at risk

Valsartan 1,541 1,504 1,442 1,258 1,093 855 689 368 368

Non-ARB 1,540 1,502 1,450 1,266 1,079 836 656 343 343

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Even

t ra

te (

%)

Valsartan arm 29 events

Non-ARB arm 48 events

HR=0.60, p=0.028

95% CI 0.38–0.95

40%

Source: Kaplan Meier Curve adopted from Dr Dahlof ESC 2006 Hotline presentationTIA events: 4 in DIOVAN group; 5 in conventional group


� The primary combined endpoint of cardiovascular morbidity and mortality was significantly reduced by 39% in those allocated to a valsartan-based regimen vs. those given conventional therapy

� There were significant reductions in the following components of the primary endpoint among those receiving a valsartan-based regimen vs. those receiving conventional therapy

� 40% risk reduction in the incidences of new or recurrent stroke (p=0.028)

� 65% risk reduction in hospitalisation for angina pectoris (p=0.001)

� 47% risk reduction in hospitalisation for heart failure (p=0.0293)

� 81% risk reduction in dissecting aortic aneurysm (p=0.0340)

JIKEI HEART Study: Main Results


Blood Pressure Results

160

140

120

100

80

00 6 12 18 24 30 36 42

Time (months)

mm

Hg

Valsartan arm (n=1,541)

Non-ARB arm (n=1,540)

SBP

DBP

Mean SBP 131 vs. 132 mmHg

Valsartan vs. non-ARB ∆n.s.

Mean DBP 77 vs. 78 mmHg

Valsartan vs. non-ARB ∆n.s.

Reductions from baseline

Valsartan Non-ARB

8.2/4.7 7.2/3.7

Note: Data shown above as text is quoted in the Lancet publication text


RationaleRationale�� AntiAnti--atherosclerotic effectsatherosclerotic effects

�� Plaque rupture reductionPlaque rupture reduction

�� Improvement in vascular endothelial functionImprovement in vascular endothelial function

�� Enhanced Enhanced fibrinolysisfibrinolysis

�� Modulation of Modulation of neurohormonallyneurohormonally--induced arterialinduced arterial

vasoconstrictionvasoconstriction

�� Blood pressure loweringBlood pressure lowering

�� LV hypertrophy reductionLV hypertrophy reduction

AngiotensinAngiotensin II reduction / II reduction / bradykininbradykinin increaseincrease

Effect beyond HT


Aggressive BP Control

131/77139/81Lancet 2007JIKEI HEART

137/78164/95Lancet 2005ASCOT-BPLA

138/79154/88Lancet 2004VALUE

145/81174/98Lancet 2002LIFE

138/82173/99Lancet 2000INSIGHT

151/88173/106Lancet 2000NORDIL

136/76145/83JAMA 2000ALLHAT

159/81194/98Lancet 1999STOP-2

150/90161/99Lancet 1999CAPPP

142/83175/105Lancet 1998HOT

Study endBaselineJournalTrial

Note: Data shown above is based on Dr Dahlof presentation at ESC 2006

19


Stroke out-come of ACE-I and ARB Rx

32.0 % RRRamiprilHOPE

25.8 % RRLosartanLIFE

20.0 % RRPerindoprilEUROPA

40.0 % RRValsartanJIKEI

28.0 % RRCandesartanSCOPE

28.0 % RRPerindopril/diureticPROGRESS

Stroke risk reductionMedicationClinical trial


Anti HT drug for first stroke prevention

29More than 115

52Up to 115

11890-110

Number needed to treat

DBP level (mmHg)

111

Sartan=��

112

Result

4% discounting, prevention of stroke,

gain of 3.7 life-year

Losartan treatment was associated with

0.059 life year gained per patient treated

Treatment with losartan compared with

atenolol may well be a cost-effective

113

COST EFFECTIVENESS

Cumulative incidence of stroke at 5.5 yeas

5145314582Net

-0.0160.0650.049

-107643933317Stroke

11281381265Medication

Costs (Euro)

Difference AtenololLosartan

114

What we learn from this topic

Primary and secondary stroke prevention by control BP is essential

Early and aggressive treatment high BP

Cut-off level of high BP for start treatment in acute stroke should be more lower than present

Target level of BP in primary and secondary prevention could be lower than present

20

115

Take home message

Effect of anti HT beyond BP lowering

Primary prevention is important

ACE –I and ARB showed more benefit in

stroke management

Early control BP in acute phase of acute

stroke may be needed and useful by ARB

116

Primary prevention is the best

117

��

Call EMS 34.65%

Observe clinical 25.20%

Call to family 26.20%

Private clinic 16.54%

Drugs store -

Massage 19.69%

Pre-test : World stroke day 25 May, 2007 at Khon Kaen, 127 elderly

118

119

Smoking cessation

– ARR 2.3%– NNT ��" 43 ��– #��$%�� ○ �� 0 &�� ○ ��'��( #��&)'�� 12,700 &��"

Secondary prevention

120

Case discussion

Female 65 yr old

Underlying HT(Rx CCB),dyslipidemia,DM

Sudden developed right hemiplegia

and global aphasia

BP 200/100 mmHg

CT brain showed normal study

( 4 hr after onset)

21

121

How to manage these problem?


Treat or Not treat BP 200/100 mmHg ?

How to treat ?

What is an anti HT ?

Why you change your clinical practice?

122

Case discussion

Women 51 yr, DM, HT, CKD

On enalapril and diovan

Sudden onset of left hemiparesis

CT-brain: lacunar infarction

BP 130/80 mmHg

Left hemiparesis, fully of consciousness

123

How to manage these problem?


Treat or Not treat BP 130/80 mmHg ?

How to treat ?

What is an anti HT ?

Why you change your clinical practice?

124

Acute ischemic stroke

No history of HTMAP 130 mmHg

Normal BPMAP 120 mmHg

High BP

Previous Rx HTMAP 140 mmHg

NPOStable, feed, oral

CCB,NTG,NPSACE-I,ARB

Normal BPHigh BP

F/U

All kinds anti HT

Prefer ACE-I, ARB

130/80 mmHg

Reduce BP 10-15%Within 24 hr

My brain mapping

125

Sociopolitical influences CPG

Political

Personal ego

Commercially fund

Pharmaceutical industry

126

1. Vemmos KN, Tsivgoulis G, Spengos K, et al. U-shaped

relationship between mortality and admission blood pressure in

patients with acute stroke. J Intern Med 2004;255:257-65.

2. Semplicini A, Maresca A, Boscolo G, et al. Hypertension in

acute ischemic stroke. Arch Intern Med 2003;163:211-6.

3. Boersma C, Carides GW, Atthobari J, et al. An economic

assessment of losartan-based versus atenolol-based therapy in

patients with hypertension and left-ventricular hypertrophy: results

from the losartan intervention for endpoint reduction (LIFE) study

adapted to the Netherlands. Clinical Therapeutics 2007;29:963-71.

References

22

127

4. Schrader J, Luders S, Kulschewski A, et al. The ACCESS study

evaluation of acute candesartan cilexetil therapy in stroke

survivors. Stroke 2003;34:1699-703.

5. Leonardi-Bee J, Phillips SJ, Sandrcock AG, The IST

Collaborative group. Blood pressure and clinical outcomes in the

international stroke trial. Stroke 2002;33:1315-20.

6. Aslanyan S, Fazekas F, Weir CJ, et al. Effect of blood pressure

during the acute period of ischemic stroke on stroke outcome a

tertiary analysis of the GAIN international trial. Stroke

2003;34:2420-5.

References

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7. Lindenauer PK, Mathew MC, Ntuli TS, et al. Use of

antihypertensive agents in the management of patients with acute

ischemic stroke. Neurology 2004;63:318-23.

8. Boreas AMHP, Lodder J, Kessels F, et al. Prognostic value of

blood pressure in acute stroke. Journal of Human Hypertension

2002;16:111-6.

9. Yamada K, Hirayama T, Hasegawa Y. Antiplatelet effect of

losartan and telmisartan in patients with ischemic stroke. Journal of

Stroke and Cerebrovascular Diseases 2007;16:225-31.

References

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10. Yong M, Diener HC, Kaste M, et al. Characteristics of blood

pressure profiles as predictors of long-term outcome after acute

ischemic stroke. Stroke 2005;36:2619-25.

11. Castillo J, Leira R, Garcia MM, et al. Blood pressure decrease

during the acute phase of ischemic stroke is associated with brain

injury and poor stroke outcome. Stroke 2004;35:520-7.

12. Stead LG, Gilmore RM, Vedula KC, et al. Impact of acute

blood pressure variability on ischemic stroke outcome. Neurology

2006;66:1878-81.

References

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131

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